Gene therapies for neurodegenerative disorders targeting ganglioside biosynthetic pathways

Abstract

A composition of matter comprising an adeno-associated virus (AAV) or other human compatible virus, encoding the gene for Sialidase Neu3, B3Galt4, St3Gal2, or combinations thereof, and a neuron specific promoter, wherein the composition is suitable for administration to a patient comprising injecting the AAV or other human compatible virus into the brain by intracranial stereotaxic injunction; wherein the AAV's encoding for the Sialidase Neu3, B3Galt4, St3Gal2, or combinations thereof enhance and/or normalize levels of GM1 in neurons, providing both therapeutic relief and disease modifying effects in specific areas of the brain relevant to particular neurodegenerative diseases.

What is claimed is: 
     
       1. A method to increase endogenous GM1 ganglioside in the brain comprising administering B3Galt4 cDNA in an expression vector to increase production of GM1 in the brain. 
     
     
       2. The method of  claim 1  further comprising administering GM1 directly to a patient suffering from a neurodegenerative disease, wherein the increase of GM1 ganglioside is targeted in the substantia nigra; wherein the direct administration provides direct increase of GM1 and the B3Galt4 cDNA provides protective and restorative effects by modulating and increasing the native production of GM1 in the brain. 
     
     
       3. The method of  claim 1  wherein the increase of GM1 ganglioside is targeted in the caudate and putamen. 
     
     
       4. The expression vector of  claim 1  being an AAV. 
     
     
       5. The expression vector of  claim 1  being a human compatible virus. 
     
     
       6. The expression vector of  claim 1  being a lentivirus. 
     
     
       7. A method for increasing the level of GM1 in the brain comprising:
 a. using an adeno-associated virus (AAV) or other human compatible virus, encoding the gene for B3Galt4 under a neuron specific promoter, and 
 b. injecting the AAV or other human compatible virus encoding the gene for B3Galt4 into the brain by intracranial stereotaxic infection; wherein the AAV's encoding the gene for B3Galt4 enhance and/or normalize levels of GM1 in neurons, providing both therapeutic relief and disease modifying effects in specific areas of the brain relevant to particular neurodegenerative diseases. 
 
     
     
       8. The method of  claim 7  wherein the injection is into the substantia nigra. 
     
     
       9. The method of  claim 7  wherein the injection is into the caudate nucleus or the caudate nucleus and the putamen. 
     
     
       10. The method of  claim 7  wherein the AAV encoding the gene for B3Galt4 is administered systemically. 
     
     
       11. The method of  claim 7  further comprising a step of administering a sialidase Neu3 sequence to said patient via an AAV or other human compatible virus. 
     
     
       12. The method of  claim 7  further comprising administering an effective amount of purified GM1 ganglioside to said patient. 
     
     
       13. The method of  claim 7 , further comprising increasing the amount of GM1 in a brain tissue comprising a concomitant treatment of a dietary supplement with complex milk lipids (CMLs) having a concentrated dietary source of GM3, to provide increased levels of substrate GM3 and GM2 for conversion to GM1, wherein the CMLs provide increased substrate to convert GM3 and GM2 to and increased expression of B3Galt4 increases conversion of GM2 to GM1 in the brain. 
     
     
       14. The method of  claim 7 , further comprising administering to said patient an effective amount of an AAV encoding for St3gal2.